1360889-95-7Relevant articles and documents
Stimulation of glucose-dependent insulin secretion by a potent, selective sst3 antagonist
Pasternak, Alexander,Feng, Zhe,De Jesus, Reynalda,Ye, Zhixiong,He, Shuwen,Dobbelaar, Peter,Bradley, Scott A.,Chicchi, Gary G.,Tsao, Kwei-Lan,Trusca, Dorina,Eiermann, George J.,Li, Cai,Feng, Yue,Wu, Margaret,Shao, Qing,Zhang, Bei B.,Nargund, Ravi,Mills, Sander G.,Howard, Andrew D.,Yang, Lihu,Zhou, Yun-Ping
, p. 289 - 293 (2012/05/31)
This letter provides the first pharmacological proof of principle that the sst3 receptor mediates glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells. To enable these studies, we identified the selective sst3 antagonist (1R,3R)-3-(5-phenyl-1H-imidazol-2-yl)-1- (tetrahydro-2H-pyran-4-yl)-2,3,4,9-tetrahydro-1H-β-carboline (5a), with improved ion channel selectivity and mouse pharmacokinetic properties as compared to previously described tetrahydro-β-carboline imidazole sst3 antagonists. We demonstrated that compound 5a enhances GSIS in pancreatic β-cells and blocks glucose excursion induced by dextrose challenge in ipGTT and OGTT models in mice. Finally, we provided strong evidence that these effects are mechanism-based in an ipGTT study, showing reduction of glucose excursion in wild-type but not sst3 knockout mice. Thus, we have shown that antagonism of sst3 represents a new mechanism with potential in treating type 2 diabetes mellitus.
